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A prenylated dsRNA sensor protects against severe COVID-19 #MMPMID34581622
Wickenhagen A; Sugrue E; Lytras S; Kuchi S; Noerenberg M; Turnbull ML; Loney C; Herder V; Allan J; Jarmson I; Cameron-Ruiz N; Varjak M; Pinto RM; Lee JY; Iselin L; Palmalux N; Stewart DG; Swingler S; Greenwood EJD; Crozier TWM; Gu Q; Davies EL; Clohisey S; Wang B; Trindade Maranhao Costa F; Freire Santana M; de Lima Ferreira LC; Murphy L; Fawkes A; Meynert A; Grimes G; Da Silva Filho JL; Marti M; Hughes J; Stanton RJ; Wang ECY; Ho A; Davis I; Jarrett RF; Castello A; Robertson DL; Semple MG; Openshaw PJM; Palmarini M; Lehner PJ; Baillie JK; Rihn SJ; Wilson SJ
Science 2021[Oct]; 374 (6567): eabj3624 PMID34581622show ga
Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that 2'-5'-oligoadenylate synthetase 1 (OAS1), through ribonuclease L, potently inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We show that a common splice-acceptor single-nucleotide polymorphism (Rs10774671) governs whether patients express prenylated OAS1 isoforms that are membrane-associated and sense-specific regions of SARS-CoV-2 RNAs or if they only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. In hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting that this antiviral defense is a major component of a protective antiviral response.